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Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass., Introduction Osteoporosis, characterized by decreased bone mineral density (BMD)and increased risk of fracture, continues to affect global health with an alarming financial and social burden. BMD is a highly heritable, [...]

Contamination of groundwater with chlorinated ethenes is common and represents a threat to drinking water sources. Standard anaerobic bioremediation methods for the highly chlorinated ethenes PCE and TCE are not always effective in promoting complete degradation. In these cases, the target contaminants are degraded to the daughter products DCE and/or vinyl chloride. This creates an additional health risk, as vinyl chloride is even more toxic and carcinogenic than its precursors. New treatment modalities are needed to deal with this widespread environmental problem. We describe successful bioremediation of a large, migrating, dilute vinyl chloride plume in Massachusetts with an aerobic biostimulation treatment approach utilizing both oxygen and ethene. Initial microcosm studies showed that adding ethene under aerobic conditions stimulated the rapid degradation of VC in site groundwater. Deployment of a full-scale treatment system resulted in plume migration cutoff and nearly complete elimination of above-standard VC concentrations. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass. [ABSTRACT FROM AUTHOR]